1

Imaging Neurodegenerative Diseases: When Should We Get Fancy?

Gil Rabinovici, MDEdward Fein & Pearl Landrith

Distinguished ProfessorUCSF Memory and Aging Center

UCSF Recent Advances in NeurologyFebruary 14, 2018

Disclosures

• Consulting/research relationships with Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Merck

• Presentation includes the amyloid tracer [11C]PIB and tau tracer [18F]AV1451 which are not FDA-approved for clinical use

• All case vignettes are based on UCSF Memory & Aging Center patients, identifying features have been modified

ARS Question #1Which of the following is TRUE about amyloid PET?A. It is investigational only and not yet FDA

approved for clinical use

B. It is a definitive diagnostic test for Alzheimer’s disease

C. Can be clinically useful in patients with cognitive impairment of uncertain etiology

D. Amyloid PET ligands bind to soluble more than fibrillar forms of Aβ

It is i

nvesti

gatio

nal only

...

It is a

definiti

ve diag

nosti...

Can be cl

inically

useful in

...

Amyloid PET lig

ands bind ..

23%

13%

60%

3%

ARS Question #2Which of the following patients would be highest priority for clinical molecular imaging?

A. Tau PET in an 84 year-old retired attorney with clinically typical Alzheimer’s disease

B. Amyloid PET in a 53 year-old commercial airline pilot with early-onset dementia

C. FDG-PET in a 45 year-old with subjective memory complaints, normal cognitive testing, and a family history of Alzheimer’s disease

D. DaTscan in a 75 year-old with cognitive decline, parkinsonism, and recurrent visual hallucinations

Tau PET

in an 84

year-o

ld...

Amyloid PET in

a 53 year..

.

FDG-PET in

a 45 year-o

ld...

DaTscan in

a 75 year-o

ld ...

0%9%

25%

66%

2

Outline

• Limitations of purely clinical diagnosis

• MRI: more than just a “rule out” test

• FDG-PET, DaTscan

• Amyloid PET– Accuracy vs. neuropathology

– Clinical applications

– Appropriate Use Criteria

– IDEAS: national study on clinical utility

• Preview of Tau imaging

Clinical Diagnosis of AD Circa 1984

McKhann et al., Neurology 1984

“Clinical criteria for AD include insidious onset and progressive impairment in memory and other cognitive functions.The diagnosis cannot be determined by laboratory tests – these tests are important primarily in identifying other causes of dementia”

1984 – 2018: Evolution of AD Biomarkers

FDGPET

StructuralMRI

AmyloidPET

CSF Aβ42, Tau, p-Tau

In 2018, diagnosis of AD is still based on clinical symptoms and cognitive testing.Laboratory tests are still used primarily to exclude other causes of dementia.

Accuracy of Clinical Diagnosis of ADU.S. Alzheimer’s Disease Centers 2005-10

• Probable AD (NINCDS-ADRDA) vs. autopsy* (n=526)– Sensitivity 71%, specificity 71%

• Clinical diagnosis of non-AD dementia vs. autopsy* (n=271)– 39% found to have primary AD post-mortem

* Based on pathologic criteria of intermediate or high-likelihood AD (NIA-Reagan: CERAD-mod or freq; Braak III-VI)

Beach et al., J Neuropathol Exp Neurol 2012

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Limitations of Clinical Diagnosis

• Same clinical phenotype can be due to multiple pathologies

• Same pathology can lead to multiple clinical phenotypes

• Clinical manifestations occur late in disease course– Long pre-clinical phase offers a therapeutic

window for early intervention

MRI: Not Just a “Rule Out” Test

• Atrophy patterns– Cortex, medial temporal,

basal ganglia, brainstem, cerebellum

• Cerebrovascular– Infarcts; white matter

hyperintensities

• Diffusion abnormalities– Cortical and subcortical

DWI in CJD

• “Pathognomonic” features– “Hummingbird” – PSP

– “Hot cross buns” - MSA

AD FTDFTD mentioned in radiology report in only 10% of patients(Suarez et al., Neurology 2009)

Desikan et al. AJNRAm J Neuroradiol. 2013

Clinical Quantitative MRI FDG-PET in Dementia Syndromes

Bohnen et al. J Nucl Med 2012

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Diagnostic Accuracy of FDG“AD” vs. “Non-AD”

Sensitivity Specificity

Silverman et al. 2001(mixed, n=138) 94% 73%

Jagust et al. 2007(mixed, n=44) 84% 74%

Minoshima et al. 2001(AD vs. DLB, n=53) 90% 80%

Foster et al. 2007(AD vs. FTD, n=45) 97% 86%

Lost in Translation?

• Comparison of FDG reads in the community to expert clinical diagnosis (Shipley et al., Neurol Clin Pract 2013)

– FDG performed in 49/1580 (3.1%)

– PET reads discordant with final expert dx in 65%

• Sources of error

– Ambiguous metabolic patterns• Very little use of SSP or other statistical displays

– Limited radiologist experience with brain PET

• 89% read by general radiologists or non-radiologists

– Non-specific or inappropriate clinical question

• 7% ordered for AD vs. FTD

Dopamine Imaging: 123I-FP-CIT SPECT (DaTscan)

• FDA approved for Parkinson’s disease vs. essential tremor

• Some studies support utility in DLB vs. AD

• More sensitive than clinical exam for dopaminergic deficit

• Not useful in identifying cause of degenerative parkinsonism (e.g. PD vs. MSA or PSP)

Normal AbnormalMcKeith et al. Lancet Neurol 2007

Pittsburgh Compound B (PIB)Amyloid plaques

Imaging Amyloid Plaques (11C-PIB PET)

Klunk et al., Ann Neurol 2004

5

NHCH3NO

OO

18F

18F-florbetapir (AmyvidTM)FDA approved April 2012

18F-flutemetamol (VizamylTM)FDA approved October 2013

18F-florbetaben (NeuraceqTM)FDA approved March 2014

Clark et al. JAMA 2011

Pathology Validation: Florbetapir PET

Amyloid PET Visual ReadsPET vs. Autopsy Studies

Gold standard: moderate- frequent neuritic plauques (CERAD)

1 – Clark et al., Lancet Neurol 20122 – Curtis et al., JAMA Neurol 20153 – http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204677s000lbl.pdf

Tracer N Report Sensitivity Specificity

Florbetapir (Amyvid)1 59 Median 92% 95%

Flutemetamol (Vizamyl)2 68 Median 88% 88%

Florbetaben (Neuraceq)3 82 Median 98% 80%

At a Loss for Words

• 57 year-old RH practicing internist with 2 years of progressive word-finding difficulties– Struggles to come up with words that

should be familiar

– Embarrassing socially and professionally

– Feels less efficient at accomplishing tasks

– No other cognitive or physical symptoms

– Has not impacted daily function

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• General physical and neurological exams wnl

• MMSE 30/30

• Fluent speech with occasional pauses; poor repetition; comprehension/reading/writing wnl

• Boston Naming Test 12/15 (normal≥14)

• Average performance for age on tests of executive functions

• Above average on verbal memory, superior visual memory

At a Loss for Words

• Basic laboratory work-up normal

• MRI: “age-appropriate global volume loss, mild periventricular white matter changes”

• Patient’s questions:– Is this normal aging?

– If not, what is the diagnosis?

• I’m worried about Alzheimer’s but my memory is fine

– Can I keep working and if so for how long?

– Should I take a cholinesterase inhibitor?

At a Loss for Words

At a loss for Words: PET Results

• Diagnosis: MCI – High likelihood due to AD (NIA-AA)

Logopenic-variant primary progressive aphasia

• Treatment– Cholinesterase inhibitor

– Referral to anti-A clinical trial

– Early retirement due to medical disability

[11C]PIB-PET[18F]FDG-PETL R L R

Amyloid Positivity in Normal Older Adults:Concept of Preclinical AD

Mintun 2006; Pike 2007; Mormino 2009 & 2011; Sperling 2011; Chételat 2012; Petersen 2015

15%-30% of cognitively normal older adults are Aβ+• More common in

ApoE4+ and older age

Aβ+ “controls” • AD-like structural

and functional brain changes

• Longitudinal cognitive decline

• Elevated risk of incident cognitive impairment

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Aβ PET+ Predicts Cognitive Decline in Aging

Donohue et al., et al., JAMA 2017

Ain’t Misbehavin’

A forgetful veteran61 yo RHM, 6 years of cognitive and behavioral changes

• First symptoms: misplacing personal items

• Increasingly repetitive; lost in familiar environments

• Disinhibited, impulsive, prone to outbursts

• Overeating, 35 lb weight gain

• h/o PTSD, EtOH abuse

Riding blind55 yo LHM, 9 yrs of personality and behavioral changes

• First symptoms: disinhibited comments to strangers

• New compulsive behaviors (sorting neighbor’s garbage)

• Skinny dipping at family beach picnic

• Pretended to be blind so that dog could ride public transit

Ain’t Misbehavin’

A forgetful veteranExam• Apathetic, slow, perseverative

• Mild limb rigidity

Neuropsych• MMSE 26/30

• Impaired executive function, episodic memory, visuospatial

• NPI 52

Differential diagnosis• Frontal-variant AD vs.

behavioral-variant FTD

Riding blindExam• Jocular, disinhibited

• Mild limb rigidity

Neuropsych• MMSE 20/30

• Impaired executive function, episodic memory, visuospatial

• NPI 46

Differential diagnosis• Frontal-variant AD vs.

behavioral-variant FTD

Differential Diagnosis: AD vs. FTD

• Ideal scenario for amyloid imaging– Clinical diagnosis is challenging

– Aβ a core feature of AD but not part of FTD pathologic spectrum (Tau or TDP-43)

– Accurate diagnosis has implications

– Early-onset dementia patients less likely to have “age-related” amyloid

– Amyloid PET outperforms FDG-PET in this scenario (Rabinovici et al., Neurology 2011)

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ARS Question #3Which patient/s do you think will be

amyloid PET positive?

A. Forgetful veteran

B. “Blind” bus rider

C. Both

D. Neither

Forge

tful v

eteran

“Blin

d” bus r

iderBoth

Neither

52%

12%

24%

12%

A forgetful veteran Riding blind

FDG FDG

PIB PIB

Follow-up

Autopsy:CBD

Follow-up

Autopsy:AD

L R L R

L R L R

Am

ylo

id p

reva

len

ce

(%

)

100

90

80

70

8080

60

50

40

30

20

10

0

AD PCA LPA FTD SD PNFA bvFTD VaD DLB PDD CBS

Clinical diagnosis

AD=Alzheimer’s disease; PCA=Posterior cortical atrophy; LPA=Logopenic aphasia; (bv)FTD= (behavioral variant) Frontotemporal dementia; SD=Semantic dementia; PNFA= Progressive non-fluent

aphasia; VaD=Vascular dementia; DLB=Dementia with Lewy bodies; PDD=Parkinson’s disease dementia; CBS=Corticobasal syndrome.

N= 1358 54 70 287 62 59 24 138 51 22 56

Ossenkoppele et al., JAMA 2015

Prevalence of Amyloid PET+in Dementia Syndromes

Positive Predictive Value of Amyloid PET Decreases with Age

Ossenkoppele et al. JAMA 2015

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Core Criteria:• Cognitive complaint with

objectively confirmed impairment

• Uncertain diagnosis (with AD as a possibility) after comprehensive evaluation by a dementia expert

• Knowledge of Aβ status expected to increase diagnostic certainty and alter management

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Top Clinical Scenarios:• Persistent/progressive

unexplained MCI

• “Possible” AD– Atypical or mixed course

– Significant co-morbidities (e.g. vascular, psychiatric, substance abuse)

• Atypically early age-of-onset (<65 years)

Johnson et al., Alzheimers Dement/J Nuc Med 2013

Inappropriate Clinical Uses

• Initial evaluation of cognitive complaints– Scan not a substitute for clinical evaluation

• Screening of cognitively normal individuals– Pre-clinical AD is a research concept only!

– Non-medical use (disability, employment)

• Differentiate AD from other Aβ diseases– Dementia with Lewy bodies; amyloid angiopathy

• Less added value in straightforward clinical cases

Johnson et al., Alzheimers Dement/J Nuc Med 2013

• National, open-label study on utility of amyloid PET in ~18,500 Medicare beneficiaries meeting AUC

• Eligible patients referred for PET by dementia experts

• Scans covered by CMS, performed and interpreted locally

• Aim 1: Impact of scan on management plan at 3 months

• Aim 2: Impact on major medical outcomes at 12 months

• The primary hypothesis is that, in diagnostically uncertain cases, amyloid PET will lead to significant changes in patient management, and this will translate into improved medical outcomes

• Secondary objectives include impact on resource utilization

IDEAS-Study@acr.orgIDEAS-Study.org

IDEAS-Study.org

18,295 scans completedMedian age 75 (65-105)

60.4% MCI39.6% dementia

PET Aβ+: MCI 55.2%Dementia 69.6%

Study closed Jan ’18Aim 1 results: early 2018Aim 2 results: mid 2019

592 dementia practices1,163 dementia experts343 PET facilities

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IDEAS-Study.org

Amyloid PET Changes Patient Management (N=3,979)

Chan

ge in

man

agem

ent c

ompo

site

(%)

0

25

50

75

Overall MCI Dementia

67.6% 67.8% 65.9%

30% goal

Rabinovici et al., AAIC 2017

Composite change in: AD medications, non-AD medications, counseling about safety and future planning

Amyloid PET vs. CSF Aβ42

Florbetapir cortical retention ratio

κ = 0.72

Both positive

Both negative Normal κ = 0.76

EMCI κ = 0.65LMCI κ = 0.71AD κ = 0.70

a

bn

orm

al

CS

F A

β1

-42

no

rma

l

Landau et al, Ann Neurol 2013

Nakamura et al., Nature 2018

Amyloid PET in Drug Development

Sevigny et al., Nature 2016

Aducanumab (humanized monoclonal Anti-Aβ antibody)Phase Ib RCT

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Landscape of Tau TracersTau PET Across Aging-AD Continuum

Scholl et al., Neuron 2016; Ossenkoppele et al., Brain 2016

Jack et al., Neurology 2016 Schonhaut et al., Ann Neurol 2017

PSP (N=33) vs. NC (46) and PD (26)

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68 yo retired NFL player with neurobehavioral decline, Aβ-neg

0.0 2.3

AV1451 SUVR

McKee CTE Stage III

Rabinovici et al., HAI 2015

ARS Question #1Which of the following is TRUE about amyloid PET?A. It is investigational only and not yet FDA

approved for clinical use

B. It is a definitive diagnostic test for Alzheimer’s disease

C. Can be clinically useful in patients with cognitive impairment of uncertain etiology

D. Amyloid PET ligands bind to soluble more than fibrillar forms of Aβ

It is i

nvesti

gatio

nal only

...

It is a

definiti

ve diag

nosti...

Can be cl

inically

useful in

...

Amyloid PET lig

ands bind ..

11%3%

82%

4%

ARS Question #2Which of the following patients would be highest priority for clinical molecular imaging?

A. Tau PET in an 84 year-old retired attorney with clinically typical Alzheimer’s disease

B. Amyloid PET in a 53 year-old commercial airline pilot with early-onset dementia

C. FDG-PET in a 45 year-old with subjective memory complaints, normal cognitive testing, and a family history of Alzheimer’s disease

D. DaTscan in a 75 year-old with cognitive decline, parkinsonism, and recurrent visual hallucinations

Tau PET

in an 84

year-o

ld...

Amyloid PE

T in a 53 yea

r...

FDG-PET in

a 45 year-o

ld...

DaTscan in

a 75 year-o

ld ...

1% 0%10%

89%

Take Home Points

• MRI can be highly informative in expert hands

• When should we get fancy in 2018?– When we are diagnostically uncertain

– When stakes of diagnosis are high

– When test likely to change management

– MAY: Mild, Atypical, Young

• Use the right test to answer your clinical question– Know the limitations of each technique

• Towards era of precision care in neurodegeneration– From clinical syndromes to molecular phenotyping

– From symptomatic therapy to early detection and prevention

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UCSF-MACBruce MillerJalayne AriasNagehan AyaktaAlexandre BejaninViktoriya BourakovaJungho ChaKiran ChaudharyLeonardo IaccarinoRenaud La JoieManja LehmannOrit Lesman-SegevRik OssenkoppeleJulie PhamDaniel SchonhautSalvatore SpinaRichard TsaiAdrienne VisaniAdam BoxerLea GrinbergMarilu Gorno-TempiniAnna KarydasJoel KramerZach MillerHowie RosenBill Seeley

FundingNIA R01-AG045611, P01-AG1972403, P50-AG023501NINDS U54NS092089Tau ConsortiumMichael J. Fox FoundationAFTDAlzheimer’s Association Avid RadiopharmaceuticalsAmerican College of RadiologyFrench Foundation

AcknowledgmentsUC Berkeley/LBNLBill JagustSuzanne BakerMustafa JanabiSam LockhartAnne MaassKris NortonJim O’NeillMichael Scholl

IDEAS Study TeamCharlie ApgarMaria CarrilloC GatsonisIlana GareenLucy HannaBruce HillnerCynthia OlsonBarry SiegelRachel Whitmer

Extra Slides

Alzheimer's & Dementia 2015

Aggregated Aβ Lesions

Diffuse Plaques Neuritic Plaques Cerebral AmyloidAngiopathy (CAA)

Slide credit: UCSF Neurodegenerative Disease Brain Bank

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Thal Phase: spatial extent of Aβ plaques

CERAD: density of neuritic plaques

Misdiagnosis Impedes Drug Development

Liu et al. Neurology 2015

Amyloid vs. FDG-PET in Differential Diagnosis of AD vs. FTD

Rabinovici et al. Neurology 2011

AD (N=62, age 65, MMSE 22)

FTD (N=45, age 65, MMSE 22)

Amyloid (PIB) PET visual reads

90% sensitivity, 83% specificity

Inter-rater agreement κ=0.96

FDG-PET visual reads

78% sensitivity*, 84% specificity

Inter-rater agreement κ=0.72*

95 autopsy-proven dementia casesPIB: Sensitivity 95%, Specificity 85%

FDG: Sensitivity 76%, Specificity 81%

* - p<0.05 vs. PIB